Identification by whole-exome sequencing of new single-nucleotide polymorphisms associated with molar-incisor hypomineralisation among the Lebanese population.

OBJECTIVE: Molar-incisor hypomineralization (MIH) is a developmental qualitative enamel defect, causing a worldwide challenging dental problem. The etiology of this defect remains unclear. Here we identify by whole-exome sequencing (WES) new single-nucleotide polymorphisms (SNPs) in genes expressed during enamel mineralization and in those modulating prenatal, natal and postnatal risk factors among the Lebanese MIH children: immune system and xenobiotic detoxification. DESIGN: Dental examination for MIH was performed based on the MIH index for diagnostic criteria. Saliva samples were collected from 37 non-related, MIH-diagnosed subjects for DNA extraction. WES was performed on the Illumina HiSeq2000 platform. The χ2 test and Fisher's exact test were used to determine relationship between SNPs frequencies and MIH. OR and its 95% CI were used to report the strength of association. The significance threshold was set at 0.05. RESULTS: Among the Lebanese population, 37 SNPs presented a significant association with MIH in the following genes: AMTN, MMP-20, STIM1, STIM2, ORAI1, SLC34A2, SLC34A3, VDR, PVALB, HSP90B1, TRPM7, SLC24A4, CA6, SLC4A2, TNFRSF11A, IL10RB, ARNT, ESR1 and CYP1B1. CONCLUSION: This is the first WES study conducted in patients with MIH. Yet, interactions between polymorphisms in different gene categories are to be investigated for a better assessment of MIH susceptibility.

Homozygous mutation in ELMO2 may cause Ramon syndrome.

We report on a girl, born to first cousin Lebanese parents, with intellectual disability, seizures, repeated gingivorrhagia, enlarged lower and upper jaws, overgrowth of the gums, high arched and narrow palate, crowded teeth, hirsutism of the back, large abdomen and a small umbilical hernia. Cysts of the mandible, fibrous dysplasia of bones, and enlarged adenoids causing around 60% narrowing of the nasopharyngeal airways were noted at radiographic examination. Her brother presented with the same features in addition to a short stature, an ostium secundum, and more pronounced intellectual disability. He died at the age of 8 years from a severe pulmonary infection and repeated bleeding episodes. A clinical diagnosis of Ramon syndrome was made. Whole exome sequencing studies performed on the family revealed the presence of a novel homozygous missense mutation in ELMO2 gene, p.I606S in the affected individuals. Loss of function mutations in ELMO2 have been recently described in another clinically distinct condition: primary intraosseous vascular malformation or intraosseous hemangioma, called VMOS. Review of the literature and differential diagnoses are discussed.

Molecular Study of Three Lebanese and Syrian Patients with Waardenburg Syndrome and Report of Novel Mutations in the EDNRB and MITF Genes.

Waardenburg syndrome (WS) is a genetic disorder characterized primarily by depigmentation of the skin and hair, heterochromia of the irides, sensorineural deafness, and sometimes by dystopia canthorum, and Hirschsprung disease. WS presents a large clinical and genetic heterogeneity. Four different types have been individualized and linked to 5 different genes. We report 2 cases of WS type II and 1 case of WS type IV from Lebanon and Syria. The genetic studies revealed 2 novel mutations in the MITF gene of the WS type II cases and 1 novel homozygous mutation in the EDNRB gene of the WS type IV case. This is the first molecular study of patients from the Arab world. Additional cases will enable a more detailed description of the clinical spectrum of Waardenburg syndrome in this region.